{"gene":"COBL","run_date":"2026-04-28T17:28:53","timeline":{"discoveries":[{"year":2011,"finding":"Cobl forms a complex with the F-BAR protein syndapin I in vivo; syndapin I recruits Cobl to membranes via its FCH-F-BAR lipid-binding domain, and this interaction is required for cortical localization of Cobl and for dendritic arbor development in neurons. Additionally, endogenous Cobl, syndapin I, and the Arp2/3 activator N-WASP were found in one complex, linking Cobl to Arp2/3-based actin dynamics.","method":"Coimmunoprecipitation, colocalization, subcellular fractionation, in vitro reconstitution, RNAi loss-of-function in neurons","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, in vitro reconstitution, and fractionation with functional neuronal phenotype; moderate-to-strong evidence from multiple orthogonal methods in one study","pmids":["21725280"],"is_preprint":false},{"year":2012,"finding":"Cobl physically associates with the F-actin-binding protein Abp1; F-actin-anchored Cobl/Abp1 complexes are critical for dendritic branching in hippocampal neurons and for Purkinje cell arborization. A Cobl mutant deficient for Abp1 binding and an Abp1 mutant lacking F-actin binding both fail to rescue respective loss-of-function phenotypes, demonstrating that both interactions are functionally required.","method":"Subcellular fractionation, protein interaction analyses, subcellular reconstitution, colocalization, gene gun transfection knockdown and rescue in neurons and tissue slices","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including rescue with binding-deficient mutants; strong mechanistic evidence","pmids":["23223303"],"is_preprint":false},{"year":2012,"finding":"In zebrafish, Cobl and syndapin I colocalize at the base of forming cilia and act together to form ciliated sensory hair cells (both kinocilia and stereocilia) in the lateral line organ. Rescue experiments showed that Cobl's syndapin I-binding Cobl homology domain and its actin-nucleating C-terminus are both required for proper sensory hair cell rosette formation.","method":"Morpholino knockdown in zebrafish, scanning electron microscopy, rescue experiments with domain-specific mutants, colocalization","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with specific morphological phenotype, domain-specific rescue, and colocalization; moderate evidence","pmids":["23203810"],"is_preprint":false},{"year":2015,"finding":"Cobl is directly regulated by Ca²⁺/Calmodulin (CaM): CaM binds Cobl at multiple sites, modulates Cobl's actin-binding properties, and promotes Cobl's interaction with syndapin I. Cobl-induced dendritic branch initiation is preceded by Ca²⁺ signals and is strictly dependent on CaM activity. CaM-binding-deficient Cobl mutants fail to rescue Cobl loss-of-function phenotypes.","method":"In vitro binding assays, CaM inhibitor studies, overexpression and rescue experiments with CaM-binding-deficient Cobl mutants in primary neurons and tissue slices, live Ca²⁺ imaging","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1-2 — direct in vitro binding, mutagenesis, and functional rescue in neurons with CaM inhibitors and mutants; multiple orthogonal methods","pmids":["26334624"],"is_preprint":false},{"year":2018,"finding":"Cobl is post-translationally regulated by arginine methylation: the protein arginine methyltransferase PRMT2 associates with Cobl via an SH3 domain-dependent interaction and methylates Cobl's actin-nucleating C-terminal domain. Methylation is required for Cobl's actin-binding activity and dendritogenesis; PRMT2's catalytic domain and SH3 domain are both required for these effects.","method":"Coprecipitation, coimmunoprecipitation, in vitro reconstitution, cellular reconstitution, gain- and loss-of-function studies in neurons, PRMT2 catalytic mutant analyses","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstitution of methylation, SH3-dependent binding, catalytic mutant rescue experiments; multiple orthogonal methods in one study","pmids":["29689199"],"is_preprint":false},{"year":2018,"finding":"Cobl acts as an effector of planar cell polarity (PCP) signaling during postnatal cochlear hair cell development. Cobl KO mice show mispositioned basal bodies and centrioles, reduced cortical F-actin beneath the sensory apparatus, and premature kinocilium retraction. The pericentriolar scaffold defects were shown to be actin polymerization dependent and calcium/calmodulin signaling dependent.","method":"Cobl knockout mice, confocal and electron microscopy, pharmacological inhibition of actin polymerization and CaM signaling","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype, pharmacological rescue demonstrating actin- and CaM-dependence; moderate-to-strong evidence","pmids":["30157434"],"is_preprint":false},{"year":2021,"finding":"Cobl and Cobl-like act interdependently in dendritic arbor development, physically linked by syndapin I. Syndapin I forms nanodomains at convex plasma membrane areas at the base of protrusive structures, and interacts with three motifs in Cobl-like, one of which is Ca²⁺/CaM-regulated. The N-terminal CaM-binding site of Cobl-like and the Ca²⁺/CaM-responsive syndapin-binding motif are critical for Cobl-like's functions, demonstrating that coordinated actin nucleation by both factors is required for dendritogenesis.","method":"Loss-of-function studies, protein interaction mapping, super-resolution microscopy of syndapin I nanodomains, rescue with domain-specific mutants","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis, domain-specific mutant rescue, nanoscale localization imaging, and functional phenotyping; multiple orthogonal methods","pmids":["34264190"],"is_preprint":false},{"year":2021,"finding":"Cobl is required for poststroke dendritic arbor repair in penumbral neurons. After middle cerebral artery occlusion, Cobl levels decline due to calpain-mediated proteolysis, but are rapidly restored by increased mRNA expression. In Cobl KO mice, the dendritic repair window (day 2–4 post-stroke) passes without any regrowth, demonstrating that Cobl's actin nucleation activity is causally required for stroke recovery.","method":"Middle cerebral artery occlusion in Cobl KO and WT mice, dendritic morphology quantification, calpain inhibition experiments, mRNA expression analysis","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype, identified molecular mechanism (calpain proteolysis, mRNA upregulation), strong causal evidence","pmids":["34898601"],"is_preprint":false},{"year":2020,"finding":"COBL interacts with and is stabilized by IGFN1 in skeletal muscle; IGFN1 and COBL colocalize at the Z-disc. IGFN1 prevents COBL from forming actin ruffles in COS7 cells, indicating IGFN1 modulates COBL's actin nucleation activity. COBL is expressed in differentiating C2C12 myoblasts but COBL loss-of-function does not abolish myoblast fusion.","method":"Pull-down with proteomics, coimmunoprecipitation, colocalization in muscle, COS7 overexpression assay, COBL KO C2C12 clones","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 3 — single pulldown with proteomics validation and functional assay, but limited mechanistic depth","pmids":["32768501"],"is_preprint":false},{"year":2025,"finding":"Cobl is expressed in ameloblasts during the secretory phase of amelogenesis and colocalizes with cortical F-actin. Cobl KO causes increased ameloblast height, altered apical F-actin density (increased at P0, reduced during maturation phase), and changes in enamel composition (increased carbon content), demonstrating that Cobl controls actin cytoskeletal organization and morphology of enamel-forming cells.","method":"Cobl KO mice, confocal microscopy with F-actin staining, morphometric analyses, energy dispersive X-ray spectroscopy for enamel composition","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined cellular and compositional phenotype; single study with multiple readouts","pmids":["40072087"],"is_preprint":false},{"year":2025,"finding":"Cobl KO mice show layer- and age-restricted deficits in cortical dendritic arborization, revealing that Cobl is required for a transient dendritic arbor expansion during emerging adulthood (layer II/III) and for associated changes in dendritic spine length. This identifies Cobl as a molecular driver of cortical rewiring during brain maturation.","method":"Cobl KO mice, dendritic morphology quantification across cortical layers and ages, Golgi staining and confocal microscopy","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype across developmental timepoints; single study","pmids":["40555515"],"is_preprint":false}],"current_model":"COBL (Cordon-Bleu) is a brain-enriched WH2 domain-based actin nucleator that requires all three of its WH2 domains for actin filament formation and whose activity is tightly controlled by multiple interacting partners and post-translational modifications: it is recruited to the plasma membrane by the F-BAR protein syndapin I (via syndapin's FCH-F-BAR domain), anchored to pre-existing F-actin by Abp1, activated by direct Ca²⁺/Calmodulin binding (which also promotes syndapin I association), and further regulated by PRMT2-mediated arginine methylation of its C-terminal actin-nucleating domain, together enabling spatiotemporally controlled cortical actin nucleation that drives dendritic branching, sensory hair cell formation, planar cell polarity maintenance, cochlear maturation, and poststroke neuronal repair."},"narrative":{"teleology":[{"year":2011,"claim":"Establishing how COBL reaches the cortex: syndapin I's F-BAR domain recruits COBL to membranes, and this complex is required for dendritic arbor formation, connecting actin nucleation to membrane geometry sensing.","evidence":"Reciprocal Co-IP, subcellular fractionation, in vitro reconstitution, and RNAi in primary neurons","pmids":["21725280"],"confidence":"High","gaps":["Stoichiometry of the COBL–syndapin I–N-WASP complex is undefined","Whether syndapin I also regulates COBL's nucleation kinetics is unknown","Mechanism by which membrane curvature feeds back on COBL activity not addressed"]},{"year":2012,"claim":"Demonstrating that COBL requires anchorage to pre-existing actin: Abp1 tethers COBL to F-actin, and both the Abp1-binding and F-actin-binding interfaces are essential for dendritic branching in hippocampal and Purkinje neurons.","evidence":"Binding-deficient mutant rescue, colocalization, and loss-of-function in neurons and tissue slices","pmids":["23223303"],"confidence":"High","gaps":["Whether Abp1 and syndapin I bind COBL simultaneously or sequentially is not resolved","Structural basis of the COBL–Abp1 interface is unknown"]},{"year":2012,"claim":"Extending COBL function beyond neurons: COBL and syndapin I cooperate at the base of forming cilia to build sensory hair cells in the zebrafish lateral line, requiring both the syndapin-binding and actin-nucleating domains.","evidence":"Morpholino knockdown in zebrafish, SEM, and domain-specific rescue","pmids":["23203810"],"confidence":"High","gaps":["Mammalian hair cell validation was pending at this time","Whether COBL nucleates actin for kinocilia versus stereocilia distinctly is unclear"]},{"year":2015,"claim":"Identifying the activating signal: Ca²⁺/calmodulin directly binds COBL at multiple sites, modulates its actin-binding properties, promotes syndapin I association, and is required for dendritic branch initiation—placing COBL under calcium signaling control.","evidence":"In vitro binding assays, CaM inhibitors, CaM-binding-deficient mutant rescue in neurons, live Ca²⁺ imaging","pmids":["26334624"],"confidence":"High","gaps":["Which CaM-binding site is most critical for nucleation versus syndapin binding is not dissected","Source of the upstream Ca²⁺ transient triggering COBL activation is not defined"]},{"year":2018,"claim":"Revealing a second regulatory layer: PRMT2 methylates arginines in COBL's C-terminal actin-nucleating domain via an SH3-dependent interaction, and this methylation is required for actin binding and dendritogenesis.","evidence":"In vitro methylation reconstitution, catalytic-dead and SH3-deletion PRMT2 mutants, gain/loss-of-function in neurons","pmids":["29689199"],"confidence":"High","gaps":["Specific arginine residues methylated and their individual contributions are not mapped","Interplay between CaM binding and arginine methylation is not addressed"]},{"year":2018,"claim":"Confirming a mammalian cilia/PCP role: COBL KO mice show mispositioned basal bodies, reduced cortical F-actin, and premature kinocilium retraction in cochlear hair cells—defects dependent on actin polymerization and CaM signaling.","evidence":"COBL KO mice, confocal and electron microscopy, pharmacological inhibition","pmids":["30157434"],"confidence":"High","gaps":["How COBL integrates into the PCP signaling cascade molecularly is not defined","Whether COBL directly interacts with PCP core components is untested"]},{"year":2020,"claim":"Indicating a role outside neurons: IGFN1 binds and stabilizes COBL at the Z-disc in skeletal muscle and suppresses COBL-driven actin ruffling, suggesting tissue-specific modulation of COBL's nucleation activity.","evidence":"Pull-down with proteomics, Co-IP, colocalization in muscle, COS7 overexpression","pmids":["32768501"],"confidence":"Medium","gaps":["Functional consequence of COBL loss in muscle differentiation is minimal","Whether IGFN1 directly inhibits WH2-mediated nucleation or sequesters COBL is unclear","Single study without independent replication of Z-disc localization"]},{"year":2021,"claim":"Establishing interdependence with a paralog: COBL and Cobl-like both require syndapin I—organized into membrane nanodomains at protrusion bases—for coordinated actin nucleation during dendritogenesis, with Ca²⁺/CaM regulating Cobl-like's syndapin-binding motif.","evidence":"Loss-of-function epistasis, super-resolution imaging, domain-specific mutant rescue","pmids":["34264190"],"confidence":"High","gaps":["Whether COBL and Cobl-like form a direct complex or work in parallel at the same site is unresolved","Relative contribution of each nucleator to actin dynamics is not quantified"]},{"year":2021,"claim":"Demonstrating a pathophysiological role: COBL is degraded by calpain after stroke but rapidly restored via mRNA upregulation; KO mice fail to regrow dendrites during the critical repair window, establishing COBL as causally required for poststroke neuronal recovery.","evidence":"MCAO in COBL KO and WT mice, dendritic morphometry, calpain inhibition, mRNA analysis","pmids":["34898601"],"confidence":"High","gaps":["Transcriptional mechanism driving rapid COBL mRNA restoration is unknown","Whether restoring COBL expression is sufficient to extend the repair window is untested"]},{"year":2025,"claim":"Broadening COBL's developmental repertoire: COBL controls apical actin organization and morphology of ameloblasts during enamel formation, with KO altering enamel mineral composition.","evidence":"COBL KO mice, F-actin staining, morphometry, energy dispersive X-ray spectroscopy","pmids":["40072087"],"confidence":"Medium","gaps":["Whether COBL's ameloblast role requires syndapin I or CaM regulation is unexplored","Mechanism linking actin disorganization to altered enamel carbon content is indirect"]},{"year":2025,"claim":"Refining the neuronal phenotype: COBL KO produces layer- and age-restricted cortical dendritic deficits, identifying COBL as a driver of a transient dendritic expansion during the transition to adulthood.","evidence":"COBL KO mice, Golgi staining, morphometry across cortical layers and ages","pmids":["40555515"],"confidence":"Medium","gaps":["Signals that restrict COBL's requirement to specific layers and ages are unknown","Behavioral consequences of the cortical arborization deficit are not characterized"]},{"year":null,"claim":"Critical open questions remain: the structural basis of COBL's three-WH2-domain nucleation mechanism, the interplay between CaM binding and PRMT2 methylation as dual activation inputs, and the identity of upstream signals that spatiotemporally control COBL in different tissues.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of COBL's actin-nucleating domain bound to actin monomers","Crosstalk between Ca²⁺/CaM activation and PRMT2-mediated methylation not tested","Upstream transcriptional and signaling pathways controlling COBL expression in non-neuronal tissues are undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,3,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,5,6]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,5,9]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[2,5]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,5,9,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5]}],"complexes":[],"partners":["PACSIN1","DBNL","PRMT2","IGFN1","COBLL1"],"other_free_text":[]},"mechanistic_narrative":"COBL (Cordon-Bleu) is a WH2-domain actin nucleator that drives cortical actin assembly to shape dendritic arbors, sensory hair cells, ameloblasts, and post-injury neuronal repair. COBL is recruited to the plasma membrane by the F-BAR protein syndapin I and anchored to pre-existing filaments by Abp1, and both interactions are required for dendritic branching in hippocampal and cerebellar neurons [PMID:21725280, PMID:23223303]. Its actin-nucleating activity is gated by direct Ca²⁺/calmodulin binding—which also enhances syndapin I association—and by PRMT2-mediated arginine methylation of the C-terminal actin-nucleating domain [PMID:26334624, PMID:29689199]. In vivo, COBL loss disrupts planar cell polarity–dependent basal body positioning in cochlear hair cells, blocks poststroke dendritic regrowth in penumbral neurons, and alters cortical dendritic arborization during brain maturation [PMID:30157434, PMID:34898601, PMID:40555515]."},"prefetch_data":{"uniprot":{"accession":"O75128","full_name":"Protein cordon-bleu","aliases":[],"length_aa":1261,"mass_kda":135.6,"function":"Plays an important role in the reorganization of the actin cytoskeleton. Regulates neuron morphogenesis and increases branching of axons and dendrites. Regulates dendrite branching in Purkinje cells (By similarity). Binds to and sequesters actin monomers (G actin). Nucleates actin polymerization by assembling three actin monomers in cross-filament orientation and thereby promotes growth of actin filaments at the barbed end. Can also mediate actin depolymerization at barbed ends and severing of actin filaments. Promotes formation of cell ruffles","subcellular_location":"Cell membrane; Cytoplasm, cytoskeleton; Cell projection, ruffle; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O75128/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/COBL","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PACSIN3","stoichiometry":4.0},{"gene":"ACTG1","stoichiometry":0.2},{"gene":"PACSIN2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/COBL","total_profiled":1310},"omim":[{"mim_id":"610318","title":"COBL-LIKE PROTEIN 1: COBLL1","url":"https://www.omim.org/entry/610318"},{"mim_id":"610317","title":"CORDON-BLEU WH2 REPEAT PROTEIN; COBL","url":"https://www.omim.org/entry/610317"},{"mim_id":"601523","title":"GROWTH FACTOR RECEPTOR-BOUND PROTEIN 10; GRB10","url":"https://www.omim.org/entry/601523"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cell Junctions","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skeletal muscle","ntpm":124.0},{"tissue":"tongue","ntpm":100.7}],"url":"https://www.proteinatlas.org/search/COBL"},"hgnc":{"alias_symbol":["KIAA0633"],"prev_symbol":[]},"alphafold":{"accession":"O75128","domains":[{"cath_id":"3.10.20.90","chopping":"56-139","consensus_level":"medium","plddt":88.8298,"start":56,"end":139},{"cath_id":"3.10.20.90","chopping":"153-230","consensus_level":"medium","plddt":88.2638,"start":153,"end":230}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75128","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75128-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75128-F1-predicted_aligned_error_v6.png","plddt_mean":50.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=COBL","jax_strain_url":"https://www.jax.org/strain/search?query=COBL"},"sequence":{"accession":"O75128","fasta_url":"https://rest.uniprot.org/uniprotkb/O75128.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75128/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75128"}},"corpus_meta":[{"pmid":"21725280","id":"PMC_21725280","title":"The functions of the actin nucleator Cobl in cellular morphogenesis critically depend on syndapin I.","date":"2011","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/21725280","citation_count":62,"is_preprint":false},{"pmid":"23223303","id":"PMC_23223303","title":"The actin nucleator Cobl is crucial for Purkinje cell development and works in close conjunction with the F-actin binding protein Abp1.","date":"2012","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23223303","citation_count":48,"is_preprint":false},{"pmid":"26334624","id":"PMC_26334624","title":"The Actin Nucleator Cobl Is Controlled by Calcium and Calmodulin.","date":"2015","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/26334624","citation_count":46,"is_preprint":false},{"pmid":"29689199","id":"PMC_29689199","title":"Arginine Methylation by PRMT2 Controls the Functions of the Actin Nucleator Cobl.","date":"2018","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/29689199","citation_count":40,"is_preprint":false},{"pmid":"26710066","id":"PMC_26710066","title":"Comprehensive Analysis of the COBRA-Like (COBL) Gene Family in Gossypium Identifies Two COBLs Potentially Associated with Fiber Quality.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26710066","citation_count":38,"is_preprint":false},{"pmid":"1732195","id":"PMC_1732195","title":"Biosynthesis of vitamin B12 in Pseudomonas denitrificans: the biosynthetic sequence from precorrin-6y to precorrin-8x is catalyzed by the cobL gene product.","date":"1992","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/1732195","citation_count":31,"is_preprint":false},{"pmid":"23203810","id":"PMC_23203810","title":"Ciliated sensory hair cell formation and function require the F-BAR protein syndapin I and the WH2 domain-based actin nucleator Cobl.","date":"2012","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/23203810","citation_count":26,"is_preprint":false},{"pmid":"29233863","id":"PMC_29233863","title":"Cobl-like promotes actin filament formation and dendritic branching using only a single WH2 domain.","date":"2017","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/29233863","citation_count":23,"is_preprint":false},{"pmid":"12514746","id":"PMC_12514746","title":"DDC and COBL, flanking the imprinted GRB10 gene on 7p12, are biallelically expressed.","date":"2002","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/12514746","citation_count":19,"is_preprint":false},{"pmid":"30157434","id":"PMC_30157434","title":"The Actin Nucleator Cobl Is Critical for Centriolar Positioning, Postnatal Planar Cell Polarity Refinement, and Function of the Cochlea.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30157434","citation_count":17,"is_preprint":false},{"pmid":"34264190","id":"PMC_34264190","title":"Functional interdependence of the actin nucleator Cobl and Cobl-like in dendritic arbor development.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34264190","citation_count":16,"is_preprint":false},{"pmid":"32768501","id":"PMC_32768501","title":"Proteomic resolution of IGFN1 complexes reveals a functional interaction with the actin nucleating protein COBL.","date":"2020","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/32768501","citation_count":13,"is_preprint":false},{"pmid":"31203879","id":"PMC_31203879","title":"Cloning of a COBL gene determining brittleness in diploid wheat using a MapRseq approach.","date":"2019","source":"Plant science : an international journal of experimental plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/31203879","citation_count":12,"is_preprint":false},{"pmid":"34800231","id":"PMC_34800231","title":"Characterization of new COBRA like (COBL) genes in wheat (Triticum aestivum) and their expression analysis under drought stress.","date":"2021","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/34800231","citation_count":11,"is_preprint":false},{"pmid":"8200543","id":"PMC_8200543","title":"Sequences of the cobalamin biosynthetic genes cobK, cobL and cobM from Rhodococcus sp. NI86/21.","date":"1994","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/8200543","citation_count":11,"is_preprint":false},{"pmid":"34898601","id":"PMC_34898601","title":"Poststroke dendritic arbor regrowth requires the actin nucleator Cobl.","date":"2021","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/34898601","citation_count":9,"is_preprint":false},{"pmid":"29198020","id":"PMC_29198020","title":"Identification of a novel intergenic miRNA located between the human DDC and COBL genes with a potential function in cell cycle arrest.","date":"2017","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29198020","citation_count":9,"is_preprint":false},{"pmid":"27419633","id":"PMC_27419633","title":"COBL is a novel hotspot for IKZF1 deletions in childhood acute lymphoblastic leukemia.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27419633","citation_count":9,"is_preprint":false},{"pmid":"30877974","id":"PMC_30877974","title":"IKZF1 Deletions with COBL Breakpoints Are Not Driven by RAG-Mediated Recombination Events in Acute Lymphoblastic Leukemia.","date":"2019","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30877974","citation_count":7,"is_preprint":false},{"pmid":"36834493","id":"PMC_36834493","title":"COBL, MKX and MYOC Are Potential Regulators of Brown Adipose Tissue Development Associated with Obesity-Related Metabolic Dysfunction in Children.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36834493","citation_count":5,"is_preprint":false},{"pmid":"38790240","id":"PMC_38790240","title":"Genome-Wide Identification and Hormone Response Analysis of the COBL Gene Family in Barley.","date":"2024","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/38790240","citation_count":3,"is_preprint":false},{"pmid":"40555515","id":"PMC_40555515","title":"Emerging Adulthood Is Marked by a Cortical Dendritic Arborization Phase Depending on the Actin Nucleator Cobl.","date":"2025","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/40555515","citation_count":0,"is_preprint":false},{"pmid":"40072087","id":"PMC_40072087","title":"The Evolutionary Young Actin Nucleator Cobl Is Important for Proper Amelogenesis.","date":"2025","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/40072087","citation_count":0,"is_preprint":false},{"pmid":"12652872","id":"PMC_12652872","title":"[Standardization of neutralization tests using the COBL cell line and comparison with the particle agglutination test for measles serology].","date":"2002","source":"Mikrobiyoloji bulteni","url":"https://pubmed.ncbi.nlm.nih.gov/12652872","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.09.25337647","title":"Machine-learning-based analysis of transcriptomics data for the identification of molecular signatures in cancer","date":"2025-10-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.09.25337647","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12711,"output_tokens":3082,"usd":0.042181},"stage2":{"model":"claude-opus-4-6","input_tokens":6436,"output_tokens":2909,"usd":0.157358},"total_usd":0.199539,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"Cobl forms a complex with the F-BAR protein syndapin I in vivo; syndapin I recruits Cobl to membranes via its FCH-F-BAR lipid-binding domain, and this interaction is required for cortical localization of Cobl and for dendritic arbor development in neurons. Additionally, endogenous Cobl, syndapin I, and the Arp2/3 activator N-WASP were found in one complex, linking Cobl to Arp2/3-based actin dynamics.\",\n      \"method\": \"Coimmunoprecipitation, colocalization, subcellular fractionation, in vitro reconstitution, RNAi loss-of-function in neurons\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, in vitro reconstitution, and fractionation with functional neuronal phenotype; moderate-to-strong evidence from multiple orthogonal methods in one study\",\n      \"pmids\": [\"21725280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cobl physically associates with the F-actin-binding protein Abp1; F-actin-anchored Cobl/Abp1 complexes are critical for dendritic branching in hippocampal neurons and for Purkinje cell arborization. A Cobl mutant deficient for Abp1 binding and an Abp1 mutant lacking F-actin binding both fail to rescue respective loss-of-function phenotypes, demonstrating that both interactions are functionally required.\",\n      \"method\": \"Subcellular fractionation, protein interaction analyses, subcellular reconstitution, colocalization, gene gun transfection knockdown and rescue in neurons and tissue slices\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including rescue with binding-deficient mutants; strong mechanistic evidence\",\n      \"pmids\": [\"23223303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In zebrafish, Cobl and syndapin I colocalize at the base of forming cilia and act together to form ciliated sensory hair cells (both kinocilia and stereocilia) in the lateral line organ. Rescue experiments showed that Cobl's syndapin I-binding Cobl homology domain and its actin-nucleating C-terminus are both required for proper sensory hair cell rosette formation.\",\n      \"method\": \"Morpholino knockdown in zebrafish, scanning electron microscopy, rescue experiments with domain-specific mutants, colocalization\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific morphological phenotype, domain-specific rescue, and colocalization; moderate evidence\",\n      \"pmids\": [\"23203810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Cobl is directly regulated by Ca²⁺/Calmodulin (CaM): CaM binds Cobl at multiple sites, modulates Cobl's actin-binding properties, and promotes Cobl's interaction with syndapin I. Cobl-induced dendritic branch initiation is preceded by Ca²⁺ signals and is strictly dependent on CaM activity. CaM-binding-deficient Cobl mutants fail to rescue Cobl loss-of-function phenotypes.\",\n      \"method\": \"In vitro binding assays, CaM inhibitor studies, overexpression and rescue experiments with CaM-binding-deficient Cobl mutants in primary neurons and tissue slices, live Ca²⁺ imaging\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct in vitro binding, mutagenesis, and functional rescue in neurons with CaM inhibitors and mutants; multiple orthogonal methods\",\n      \"pmids\": [\"26334624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cobl is post-translationally regulated by arginine methylation: the protein arginine methyltransferase PRMT2 associates with Cobl via an SH3 domain-dependent interaction and methylates Cobl's actin-nucleating C-terminal domain. Methylation is required for Cobl's actin-binding activity and dendritogenesis; PRMT2's catalytic domain and SH3 domain are both required for these effects.\",\n      \"method\": \"Coprecipitation, coimmunoprecipitation, in vitro reconstitution, cellular reconstitution, gain- and loss-of-function studies in neurons, PRMT2 catalytic mutant analyses\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution of methylation, SH3-dependent binding, catalytic mutant rescue experiments; multiple orthogonal methods in one study\",\n      \"pmids\": [\"29689199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cobl acts as an effector of planar cell polarity (PCP) signaling during postnatal cochlear hair cell development. Cobl KO mice show mispositioned basal bodies and centrioles, reduced cortical F-actin beneath the sensory apparatus, and premature kinocilium retraction. The pericentriolar scaffold defects were shown to be actin polymerization dependent and calcium/calmodulin signaling dependent.\",\n      \"method\": \"Cobl knockout mice, confocal and electron microscopy, pharmacological inhibition of actin polymerization and CaM signaling\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype, pharmacological rescue demonstrating actin- and CaM-dependence; moderate-to-strong evidence\",\n      \"pmids\": [\"30157434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cobl and Cobl-like act interdependently in dendritic arbor development, physically linked by syndapin I. Syndapin I forms nanodomains at convex plasma membrane areas at the base of protrusive structures, and interacts with three motifs in Cobl-like, one of which is Ca²⁺/CaM-regulated. The N-terminal CaM-binding site of Cobl-like and the Ca²⁺/CaM-responsive syndapin-binding motif are critical for Cobl-like's functions, demonstrating that coordinated actin nucleation by both factors is required for dendritogenesis.\",\n      \"method\": \"Loss-of-function studies, protein interaction mapping, super-resolution microscopy of syndapin I nanodomains, rescue with domain-specific mutants\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis, domain-specific mutant rescue, nanoscale localization imaging, and functional phenotyping; multiple orthogonal methods\",\n      \"pmids\": [\"34264190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cobl is required for poststroke dendritic arbor repair in penumbral neurons. After middle cerebral artery occlusion, Cobl levels decline due to calpain-mediated proteolysis, but are rapidly restored by increased mRNA expression. In Cobl KO mice, the dendritic repair window (day 2–4 post-stroke) passes without any regrowth, demonstrating that Cobl's actin nucleation activity is causally required for stroke recovery.\",\n      \"method\": \"Middle cerebral artery occlusion in Cobl KO and WT mice, dendritic morphology quantification, calpain inhibition experiments, mRNA expression analysis\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype, identified molecular mechanism (calpain proteolysis, mRNA upregulation), strong causal evidence\",\n      \"pmids\": [\"34898601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"COBL interacts with and is stabilized by IGFN1 in skeletal muscle; IGFN1 and COBL colocalize at the Z-disc. IGFN1 prevents COBL from forming actin ruffles in COS7 cells, indicating IGFN1 modulates COBL's actin nucleation activity. COBL is expressed in differentiating C2C12 myoblasts but COBL loss-of-function does not abolish myoblast fusion.\",\n      \"method\": \"Pull-down with proteomics, coimmunoprecipitation, colocalization in muscle, COS7 overexpression assay, COBL KO C2C12 clones\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single pulldown with proteomics validation and functional assay, but limited mechanistic depth\",\n      \"pmids\": [\"32768501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cobl is expressed in ameloblasts during the secretory phase of amelogenesis and colocalizes with cortical F-actin. Cobl KO causes increased ameloblast height, altered apical F-actin density (increased at P0, reduced during maturation phase), and changes in enamel composition (increased carbon content), demonstrating that Cobl controls actin cytoskeletal organization and morphology of enamel-forming cells.\",\n      \"method\": \"Cobl KO mice, confocal microscopy with F-actin staining, morphometric analyses, energy dispersive X-ray spectroscopy for enamel composition\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular and compositional phenotype; single study with multiple readouts\",\n      \"pmids\": [\"40072087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cobl KO mice show layer- and age-restricted deficits in cortical dendritic arborization, revealing that Cobl is required for a transient dendritic arbor expansion during emerging adulthood (layer II/III) and for associated changes in dendritic spine length. This identifies Cobl as a molecular driver of cortical rewiring during brain maturation.\",\n      \"method\": \"Cobl KO mice, dendritic morphology quantification across cortical layers and ages, Golgi staining and confocal microscopy\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype across developmental timepoints; single study\",\n      \"pmids\": [\"40555515\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"COBL (Cordon-Bleu) is a brain-enriched WH2 domain-based actin nucleator that requires all three of its WH2 domains for actin filament formation and whose activity is tightly controlled by multiple interacting partners and post-translational modifications: it is recruited to the plasma membrane by the F-BAR protein syndapin I (via syndapin's FCH-F-BAR domain), anchored to pre-existing F-actin by Abp1, activated by direct Ca²⁺/Calmodulin binding (which also promotes syndapin I association), and further regulated by PRMT2-mediated arginine methylation of its C-terminal actin-nucleating domain, together enabling spatiotemporally controlled cortical actin nucleation that drives dendritic branching, sensory hair cell formation, planar cell polarity maintenance, cochlear maturation, and poststroke neuronal repair.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"COBL (Cordon-Bleu) is a WH2-domain actin nucleator that drives cortical actin assembly to shape dendritic arbors, sensory hair cells, ameloblasts, and post-injury neuronal repair. COBL is recruited to the plasma membrane by the F-BAR protein syndapin I and anchored to pre-existing filaments by Abp1, and both interactions are required for dendritic branching in hippocampal and cerebellar neurons [PMID:21725280, PMID:23223303]. Its actin-nucleating activity is gated by direct Ca²⁺/calmodulin binding—which also enhances syndapin I association—and by PRMT2-mediated arginine methylation of the C-terminal actin-nucleating domain [PMID:26334624, PMID:29689199]. In vivo, COBL loss disrupts planar cell polarity–dependent basal body positioning in cochlear hair cells, blocks poststroke dendritic regrowth in penumbral neurons, and alters cortical dendritic arborization during brain maturation [PMID:30157434, PMID:34898601, PMID:40555515].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing how COBL reaches the cortex: syndapin I's F-BAR domain recruits COBL to membranes, and this complex is required for dendritic arbor formation, connecting actin nucleation to membrane geometry sensing.\",\n      \"evidence\": \"Reciprocal Co-IP, subcellular fractionation, in vitro reconstitution, and RNAi in primary neurons\",\n      \"pmids\": [\"21725280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry of the COBL–syndapin I–N-WASP complex is undefined\",\n        \"Whether syndapin I also regulates COBL's nucleation kinetics is unknown\",\n        \"Mechanism by which membrane curvature feeds back on COBL activity not addressed\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating that COBL requires anchorage to pre-existing actin: Abp1 tethers COBL to F-actin, and both the Abp1-binding and F-actin-binding interfaces are essential for dendritic branching in hippocampal and Purkinje neurons.\",\n      \"evidence\": \"Binding-deficient mutant rescue, colocalization, and loss-of-function in neurons and tissue slices\",\n      \"pmids\": [\"23223303\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether Abp1 and syndapin I bind COBL simultaneously or sequentially is not resolved\",\n        \"Structural basis of the COBL–Abp1 interface is unknown\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extending COBL function beyond neurons: COBL and syndapin I cooperate at the base of forming cilia to build sensory hair cells in the zebrafish lateral line, requiring both the syndapin-binding and actin-nucleating domains.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish, SEM, and domain-specific rescue\",\n      \"pmids\": [\"23203810\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mammalian hair cell validation was pending at this time\",\n        \"Whether COBL nucleates actin for kinocilia versus stereocilia distinctly is unclear\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying the activating signal: Ca²⁺/calmodulin directly binds COBL at multiple sites, modulates its actin-binding properties, promotes syndapin I association, and is required for dendritic branch initiation—placing COBL under calcium signaling control.\",\n      \"evidence\": \"In vitro binding assays, CaM inhibitors, CaM-binding-deficient mutant rescue in neurons, live Ca²⁺ imaging\",\n      \"pmids\": [\"26334624\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Which CaM-binding site is most critical for nucleation versus syndapin binding is not dissected\",\n        \"Source of the upstream Ca²⁺ transient triggering COBL activation is not defined\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealing a second regulatory layer: PRMT2 methylates arginines in COBL's C-terminal actin-nucleating domain via an SH3-dependent interaction, and this methylation is required for actin binding and dendritogenesis.\",\n      \"evidence\": \"In vitro methylation reconstitution, catalytic-dead and SH3-deletion PRMT2 mutants, gain/loss-of-function in neurons\",\n      \"pmids\": [\"29689199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific arginine residues methylated and their individual contributions are not mapped\",\n        \"Interplay between CaM binding and arginine methylation is not addressed\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Confirming a mammalian cilia/PCP role: COBL KO mice show mispositioned basal bodies, reduced cortical F-actin, and premature kinocilium retraction in cochlear hair cells—defects dependent on actin polymerization and CaM signaling.\",\n      \"evidence\": \"COBL KO mice, confocal and electron microscopy, pharmacological inhibition\",\n      \"pmids\": [\"30157434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How COBL integrates into the PCP signaling cascade molecularly is not defined\",\n        \"Whether COBL directly interacts with PCP core components is untested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Indicating a role outside neurons: IGFN1 binds and stabilizes COBL at the Z-disc in skeletal muscle and suppresses COBL-driven actin ruffling, suggesting tissue-specific modulation of COBL's nucleation activity.\",\n      \"evidence\": \"Pull-down with proteomics, Co-IP, colocalization in muscle, COS7 overexpression\",\n      \"pmids\": [\"32768501\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of COBL loss in muscle differentiation is minimal\",\n        \"Whether IGFN1 directly inhibits WH2-mediated nucleation or sequesters COBL is unclear\",\n        \"Single study without independent replication of Z-disc localization\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Establishing interdependence with a paralog: COBL and Cobl-like both require syndapin I—organized into membrane nanodomains at protrusion bases—for coordinated actin nucleation during dendritogenesis, with Ca²⁺/CaM regulating Cobl-like's syndapin-binding motif.\",\n      \"evidence\": \"Loss-of-function epistasis, super-resolution imaging, domain-specific mutant rescue\",\n      \"pmids\": [\"34264190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether COBL and Cobl-like form a direct complex or work in parallel at the same site is unresolved\",\n        \"Relative contribution of each nucleator to actin dynamics is not quantified\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating a pathophysiological role: COBL is degraded by calpain after stroke but rapidly restored via mRNA upregulation; KO mice fail to regrow dendrites during the critical repair window, establishing COBL as causally required for poststroke neuronal recovery.\",\n      \"evidence\": \"MCAO in COBL KO and WT mice, dendritic morphometry, calpain inhibition, mRNA analysis\",\n      \"pmids\": [\"34898601\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Transcriptional mechanism driving rapid COBL mRNA restoration is unknown\",\n        \"Whether restoring COBL expression is sufficient to extend the repair window is untested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Broadening COBL's developmental repertoire: COBL controls apical actin organization and morphology of ameloblasts during enamel formation, with KO altering enamel mineral composition.\",\n      \"evidence\": \"COBL KO mice, F-actin staining, morphometry, energy dispersive X-ray spectroscopy\",\n      \"pmids\": [\"40072087\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether COBL's ameloblast role requires syndapin I or CaM regulation is unexplored\",\n        \"Mechanism linking actin disorganization to altered enamel carbon content is indirect\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Refining the neuronal phenotype: COBL KO produces layer- and age-restricted cortical dendritic deficits, identifying COBL as a driver of a transient dendritic expansion during the transition to adulthood.\",\n      \"evidence\": \"COBL KO mice, Golgi staining, morphometry across cortical layers and ages\",\n      \"pmids\": [\"40555515\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Signals that restrict COBL's requirement to specific layers and ages are unknown\",\n        \"Behavioral consequences of the cortical arborization deficit are not characterized\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Critical open questions remain: the structural basis of COBL's three-WH2-domain nucleation mechanism, the interplay between CaM binding and PRMT2 methylation as dual activation inputs, and the identity of upstream signals that spatiotemporally control COBL in different tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of COBL's actin-nucleating domain bound to actin monomers\",\n        \"Crosstalk between Ca²⁺/CaM activation and PRMT2-mediated methylation not tested\",\n        \"Upstream transcriptional and signaling pathways controlling COBL expression in non-neuronal tissues are undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 5, 6]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 5, 9]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 5, 9, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PACSIN1\",\n      \"DBNL\",\n      \"PRMT2\",\n      \"IGFN1\",\n      \"COBLL1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}